An HIV infection cycle begins with the entry of an HIV virus into a target cell. Entry commences when an HIV envelope glycoprotein (env) binds to a human CD4 molecule in a target cell membrane. This binding leads to fusion of virus and cell membranes, which in turn facilitates virus entry into the host. The HIV-infected host cell eventually expresses env on its surface. This expression allows the infected cell to fuse with uninfected, CD4-positive cells, thereby spreading the virus.
Recent studies have shown that the HIV fusion process occurs with a wide range of human cell types that either express human CD4 endogenously or that have been engineered to express human CD4. The fusion process, however, does not occur with nonhuman cell types engineered to express human CD4 even though these nonhuman cells still can bind env. The disparity between human and nonhuman cell types exists because membrane fusion requires the coexpression of human CD4 and one or more cofactors specific to human cell types. Nonhuman cell types that have been engineered to express human CD4 but not the additionally required factor(s) are incapable of membrane fusion, and therefore are nonpermissive for HIV infection.
Some individual HIV isolates, designated “macrophage-tropic,” efficiently infect primary macrophages but not immortalized T-cell lines. Other isolates, designated “T-cell line-tropic,” have the opposite property and infect immortalized T-cell lines more efficiently than they infect primary macrophages. Both types of isolates readily infect primary T-cells from the body, however. The selective tropism of these two types of isolates is thought to be due to their requirements for distinct cofactors that are differentially expressed on different CD4 positive cell types. It should be understood that other HIV strains are “dual-tropic” and have the ability to infect both macrophages and immortalized T-cell lines and are believed to be able to use more than one cofactor.
Recently a cofactor required for fusion of virus and cell membranes has been described. Feng et al., Science 272: 872-7 (1996). This factor, called “fusin,” (also known as CXCR4) permits cells that contain human CD4 to fuse with the surface of an HIV virus. Fusin functions preferentially for T-cell line-tropic HIV-1 isolates and much less well for macrophage-tropic HIV-1 isolates.
The discovery of fusin allows the creation of a successful small animal model. Such a model is crucial for studies of HIV infection and of the effectiveness of anti-HIV therapeutics. But the presence of fusin enables the study of T-cell line-tropic but not macrophage-tropic isolates. This is an important distinction because macrophage-tropic isolates represent the predominant type of isolates obtained from infected individuals. Macrophage-tropic isolates also appear to be preferentially transmitted between individuals. A putative cofactor that is necessarily expressed with CD4 to allow entry of macrophage-tropic isolates remains unknown.
In recent years, researchers have bred transgenic animals that contain cells which express human CD4 and which could be used as models for HIV infection of macrophages if the macrophage-specific factor were known. See, for example, Dunn et al., Human immunodeficiency virus type 1 infection of human CD4-transgenic rabbits, J. Gen. Vir. 76:1327-1336 (1995); Snyder et al., Development and Tissue-Specific Expression of Human CD4 in Transgenic Rabbits, Mol. Reprod. & Devel. 40:419428 (1995); Killeen et al., Regulated Expression of Human CD4 Rescues Helper T-Cell Development in Mice Lacking Expression of Endogenous CD4, EMBO J. 12:1547-1553 (1993); Forte et al., Human CD4 Produced in Lymphoid Cells of Transgenic Mice Binds HIV gp120 and Modifies the Subsets of Mouse T-Cell Populations, Immunogenetics 38:455-459 (1993).
A goal of research in this field is to find a putative factor for the macrophage-tropic isolates that could be co-expressed with CD4 in a small animal. Such co-expression would provide an animal model to develop efficacious therapies to combat infection by macrophage-tropic HIV isolates. The discovery of other essential cofactors would provide new targets for development of anti-HIV therapies.